Organization of the human genome Genome structure Nuclear vs. mitochondrial genomes Gene families Transposable elements Other repeated sequences

Organization of the human genome Mitochondrial genome: Origin Endosymbiont Hypothesis Ancient archaeal cell engulfed a proteobacterium and eventually came to rely on the symbiont for survival. Evidence Circular genome Autonomous ribosomes

Organization of the human genome Mitochondrial genome Small (16.5 kb) circular DNA 1 gene/0.45 kb Very few repeats No introns 93% coding Heavy and Light strands

Organization of the human genome Mitochondrial genes rRNA, tRNA and protein encoding genes (37) 28 encoded by the heavy strand 24 RNA products and (23s, 16s, tRNAs) 13 protein coding genes

Organization of the human genome Mitochondrial genes rRNA, tRNA and protein encoding genes (37) 28 encoded by the heavy strand 24 RNA products and (23s, 16s, tRNAs) 13 protein coding genes Genes are transcribed as two transcription units and cleaved afterwards Genes may overlap

Organization of the human genome Limited autonomy of mt genomes mt encoded nuclear NADH dehydrog 7 subunits >41 subunits Succinate CoQ red 0 subunits 4 subunits Cytochrome b-c1 comp 1 subunit 10 subunits Cytochrome C oxidase 3 subunits 10 subunits ATP synthase complex 2 subunits 14 subunits tRNA components 22 tRNAs none rRNA components 2 components none Ribosomal proteins none ~80 Other mt proteins none mtDNA pol, RNA pol etc.

Organization of the human genome Special Features Mitochondrial genetic code (reduced selection) Two extra stop codons: AGA and AGG UGA = tryptophan, AUA = Methionine/start No recombination Maternal inheritance

Organization of the human genome Mitochondrial genome replication OH – Origin of heavy strand replication OL – Origin of light strand replication D-loop

Organization of the human genome Nuclear genome 3300 Mb 23 (XX) or 24 (XY) linear chromosomes 30-35,000 genes 1 gene/40kb Introns 3% coding Repetitive DNA sequences (45%) Recombination Mendelian inheritance (X + auto, paternal Y)

Organization of the human genome Contrasting gene densities Some regions of the genome are gene-rich and others are gene-poor HLA high density Dystrophin low density

Organization of the human genome Gene families Thought to be generated by gene duplication Functionally similar genes are occasionally clustered, but usually dispersed throughout the genome

Histone gene distribution

Organization of the human genome Genes vary in size and exon content A general inverse relationship.

09_07.jpg 09_07.jpg Exon content vs. length

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Organization of the human genome Genes within genes Intron 26 of the NF1 gene contains three internal genes.

Organization of the human genome Gene families: defined by extensive DNA similarity Alpha and Beta globin genes defined by large highly conserved domains defined by conserved amino acid motifs DEAD box WD repeats

Organization of the human genome Superfamilies Common structural features Ig superfamily Cell surface receptors

Organization of the human genome Clustered gene families Single clusters (sometimes tandem) Growth hormone 5 copies (67kb) a-globin 7 copies (50kb) multiple clusters (sometimes tandem) Hox genes (multi) 38 four clusters Olfactory receptors 1000 in 25 large clusters

Organization of the human genome Interspersed gene families generated by: Nuclear translocation Gene/genome duplication Pax 9 copies Actin >20 copies retrotransposition events Alu elements (repeats) 1.1 million LINE elements (L1) 200-500,000

Organization of the human genome HLA heavy chain gene cluster: an example Gene fragments Pseudogenes Truncated genes

Organization of the human genome Processed pseudogenes Originate by reverse transcription of a processed transcript TPRT

Organization of the human genome Repetitive DNA Micro and minisatellites Retrotransposons (LINEs and SINEs) Chromosomal location of repeats Telomeres Centromeres

Organization of the human genome Formation of higher order repeat units

Organization of the human genome Human transposable elements

Organization of the human genome Transposable elements with RNA intermediates Endogenous retroviruses Retrotransposons Retropseudogenes

SINE Mobilization – “Copy and Paste” Reverse transcription and insertion Pol III transcription 1. Usually a single ‘master’ copy 2. Pol III transcription to an RNA intermediate 3. Target primed reverse transcription (TPRT) – enzymatic machinery provided by LINEs

Organization of the human genome Human transposable elements Alu elements LINE elements

Organization of the human genome Mobile elements and gene structure RB1 region Alu LINE Simple sequence repeats